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Publicly Funded Clinical Trials and
the Future of Cancer Care
SWOG 60th Anniversary Meeting
Richard L. Schilsky, M.D., FACP, FASCO
Senior Vice President and Chief Medical Officer
American Society of Clinical Oncology
Past Group Chair, Cancer and Leukemia Group B
Key Events Prior to 1955
• 1912 Congress establishes Public Health Service
• 1937 Congress establishes National Cancer Institute
within PHS
• 1948 Congress establishes National Institutes of
Health
• 1953 James Holland begins trials in acute leukemia at
NCI
1956
• Senate Appropriations Committee instructs NCI to establish
“Cooperative System”
• Three groups established:
– Acute Leukemia Group A
Joseph Burchenal
– Acute Leukemia Group B
Emil Frei
– Eastern Solid Tumor Group
Gordon Zubrod
ALGB: 1956-58
“This work is one of the first
comparative studies in the
chemotherapy of malignant
neoplastic disease.”
8 page protocol
Launched 1956
Published 1958
Cooperative Group Program: 2011
National Clinical Trials Network
Goals of Therapeutic Clinical Trials
Commercial Sponsor
Public Sponsor
Goals of Therapeutic Clinical Trials
Commercial Sponsor
Public Sponsor
Drug Registration
Optimize Treatment
Goals of Therapeutic Clinical Trials
Commercial Sponsor
Public Sponsor
Drug Registration
Optimize Treatment
Label Extension
Label Extension
Goals of Therapeutic Clinical Trials
Commercial Sponsor
Public Sponsor
Drug Registration
Optimize Treatment
Label Extension
Label Extension
Expand Market Share
Create New Knowledge
Goals of Therapeutic Clinical Trials
Commercial Sponsor
Public Sponsor
Drug Registration
Optimize Treatment
Label Extension
Label Extension
Expand Market Share
Create New Knowledge
Create Shareholder Value
Improve Public Health
Why Publicly Funded Trials are Important
• Compare the effectiveness of various treatment options
• Combine/compare drugs developed by different sponsors
• Develop therapies for rare diseases
• Address optimal dosing
• Test multi-modality therapies such as radiation therapy in
combination with drugs
• Identify patient and tumor subsets most likely to benefit from
interventions
Why Publicly Funded Trials are Important
• Study screening and prevention strategies
• Focus on survivorship and quality of life
• Publish negative results
• Assess cost and cost-effectiveness
• Provide “gold standard” databases for registry studies
Comparing Efficacy
SWOG Comparison of Lymphoma Treatments
Fisher R et al. N Engl J Med 1993;328:1002-1006
ECOG Comparison of Chemotherapy
Regimens for NSCLC
Schiller J et al. N Engl J Med 2002;346:92-98
ECOG 4599 Carboplatin-Paclitaxel +/Bevacizumab in Advanced NSCLC
Sandler A et al. N Engl J Med 2006;355:2542-2550.
Compare Treatments from Different
Sponsors
CALGB/SWOG 80405
Bevacizumab
R
A
N
D
O
M
I
Z
E
FOLFOX 6
or FOLFIRI*
Cetuximab
*M.D. Choice
Bevacizumab
+ Cetuximab
CALGB/SWOG 80405
Roche
R
A
N
D
O
M
I
Z
E
FOLFOX 6
or FOLFIRI*
BMS
*M.D. Choice
Bevacizumab
+ Cetuximab
Evolution of CALGB / SWOG
80203/80405 Study Design
Suspended
6/08 after
presentation
of KRAS Mut
ORIGINAL 80405
Data
Activated 9/05
CHEMO +
BEV v. CETUX v.
BEV / CETUX
2003
2005 – 08
KRAS WT
DELETE COMBO
2008-09
Final Design
Re-activated
5/09
2010-2012
2013
1/2014
DATA RELEASE
80203 Chemo Bev FDA
+/- Cetux
Approved 2/04;
Activated 12/03 80203 Closed 1/05
Presented by:
CALGB/SWOG 80405: Overall Survival
Arm
Chemo +
Cetux
N (Events)
OS (m)
Median
95% CI
578 (375) 29.9
27.0-32.9
Chemo + Bev 559 (371) 29.0
25.7-31.2
P=0.34
HR 0.925 (0.78-1.09)
CALGB 40502
R
a
n
d
o
m
i
z
e
Paclitaxel d 1,8,15
q 28d + Bev
Ixabepilone d 1,8,15 q 28d
+Bev
Pre-Rx
CTC
sampling
Re-stage q 3 cycles
until PD
nab-Paclitaxel d 1,8,15
q 28d + Bev
D1 C2
D1 C3
D1 Q 3C
PD
CALGB 40502
R
a
n
d
o
m
i
z
e
Generic
Bristol Myers Squib
Pre-Rx
CTC
sampling
Re-stage q 3 cycles
until PD
Abraxis
D1 C2
D1 C3
D1 Q 3C
PD
Ixabepilone or Nab-paclitaxel Compared
with Paclitaxel in Advanced Breast Cancer
Hope S. Rugo et al. JCO 2015;33:2361-2369
Rare Disease Treatments
5-Azacitidine in MDS
Silverman, L. R. et al. J Clin Oncol; 20:2429-2440 2002
PCV in Grade 2 Glioma: An NRG Study 18
Years in the Making!
Buckner JC et al. N Engl J Med 2016;374:1344-1355.
Optimize Dosing
GOG 172: IP vs IV Cisplatin plus Paclitaxel
in Advanced Ovarian Cancer
Armstrong D et al. N Engl J Med 2006;354:34-43
GOG 252: Progression Free Survival
Optimal Stage II-III
CALGB 9741: Dose Dense Adjuvant
Chemotherapy for Breast Cancer
Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003
0.8
0.6
0.4
0.2
0.0
Proportion Disease-Free
CALGB 9741: Disease-Free Survival
By Density
0
2
4
6
8
10
Years From Study Entry
2 wks
3 wks
N= 988
N= 984
Events= 270
Events= 328
Median= NA
Median= NA
Chi-square=
p-value=
8.1244
0.0044
0.6
0.4
0.0
0.2
Proportion Surviving
0.8
CALGB 9741: Overall Survival
By Density
0
2
4
6
8
10
Years From Study Entry
2 wks
3 wks
N= 988
N= 984
Events= 220
Events= 266
Median= NA
Median= NA
Chi-square=
p-value=
5.6016
0.0179
Improvement in Outcome Over Time:
Results of COG Studies of ALL
100
1996-2000
(n=3421)
1989-1995
(n=5121)
80
1983-1988
(n=3711)
% Surviving
60
1978-1983
(n=2984)
1975-1977
(n=1313)
40
1972-1975
(n=936)
1970-1972
(n=499)
20
1968-1970
(n=402)
0
0
2
4
6
8
10
Years
12
14
16
18
Combine Treatment Modalities
Intergroup Gastric Adjuvant Study
Smalley S R et al. JCO 2012;30:2327-2333
RTOG 9111 Larynx Preservation
Forastiere A et al. N Engl J Med 2003;349:2091-2098
Identify Patient Subsets
AML Subtypes
Mrozek, Marcucci, & Bloomfield. Blood 2007;109:431-448
Study Prevention Strategies
STAR Breast Cancer Prevention Trial
Cumulative Incidence of Invasive and Noninvasive Breast Cancer
2010 Update: Tamoxifen superior to
raloxifene in reducing risk of invasive
breast cancer, RR 1.24, p=0.01
Invasive Cancer
Vogel, V. G. et al. JAMA 2006;295:2727-2741.
Non Invasive Cancer
STAR Trial Adverse Events
2010 Update: Tamoxifen increases
risk of invasive uterine cancer (RR
0.55, p=0.003) and of thrombotic
events (RR 0.75, p=.007)
Uterine Cancer
Vogel, V. G. et al. JAMA 2006;295:2727-2741.
Thromboembolism
Publish Negative Results
CALGB 9082 High Dose Chemotherapy
for High Risk Breast Cancer
Peters, W. P. et al. J Clin Oncol; 23:2191-2200 2005
CALGB 9082 Outcomes
Peters, W. P. et al. J Clin Oncol; 23:2191-2200 2005
Exploratory (Correlative)
Biomarker Studies
CALGB 89803: Disease-Free Survival
Saltz, L. B. et al. J Clin Oncol; 25:3456-3461 2007
KRAS Mutation is Not Prognostic in Stage
III Colon Cancer: CALGB 89803
Ogino S et al. Clin Cancer Res 2009;15:7322-7329
BRAF Mutation is Prognostic in Stage III
Colon Cancer: CALGB 89803
Ogino S et al. Clin Cancer Res 2012;18:890-900
Biomarker-Drug Co-Development
CALGB 10603
F
L
T
Flt 3
ITD
S
c
r
e
e
n
i
n
g
R
e
g
i
s
t
e
r
R
a
n
d
o
m
i
z
e
Maintenance
Placebo
Chemotherapy
+ Placebo
Chemotherapy
+ Midostaurin
Maintenance
Midostaurin
Whitman, S. P. et al. Cancer Res 2001;61:7233-7239
Overall Survival
23% reduced risk of death in the Mido arm
Arm
4-year Survival
MIDO
51.4% (95%CI: 46, 57)
PBO
44.2% (95%CI: 39, 50)
+ Censor
Hazard Ratio*: 0.77
1-sided log-rank p-value*: 0.0074
Median OS: Mido 74.7 (31.7-NE); PBO 25.6 (18.6-42.9) months
NE: not estimable
* controlled for FLT3 subtype (TKD, ITD-Low, ITD-High)
Marker Validation Studies
TailoRx
NODE NEGATIVE BREAST CANCER STUDY
ER/PR + tumors
ONCOTYPE DX ASSAY
Score < 11
29% of pts
Score 11-25
44% of pts
Score >25
27% of pts
R
Endocrine
Therapy
Endocrine
+
Chemotherapy
Chemotherapy +
Endocrine Therapy
Accrual goal= 4800 randomized patients, 11000 screened
Non inferiority = decrease in 5 year DFS from 90 to 87% or less
NEXTGEN NCTN TRIALS
Asking Key Questions
• Can we improve patient outcomes by
matching treatments to genomic signatures?
• Can we generate informative signals of
activity by allocating patients to drugs based
on genomic signatures?
NCI-MATCH Schema (EAY131)
58
Lung-MAP Study (SWOG)
Herbst et al. Clin Cancer Res 2015;21:1514-1524
©2015 by American Association for Cancer Research
ALCHEMIST (ECOG-ACRIN/ALLIANCE)
M-PACT Study
Summary
• Cooperative groups have conducted practice-changing
clinical trials for 60 years!
• Publicly funded clinical trials are essential to:
- directly compare drug treatments;
- develop combined modality treatments;
- study chemoprevention and rare diseases;
- identify patient subsets;
- study health outcomes, cost and cost effectiveness
- define the role of precision medicine approaches in
cancer management
ASCO and the NCTN
• Advocate for federal funding
• Educate about the importance of publically-funded clinical
trials
• Disseminate research findings
• Train sites/research staff in best practices
• Recognize clinical trial participation
• Monitor NCI management
• Support simplification of regulatory oversight
THANK YOU AND HAPPY
ANNIVERSARY SWOG!